Total synthesis of merrilactone A

ABSTRACT

This invention provides a total synthesis of Merrillactone and Merrilactone analogues having the structure  
                 
 
     wherein Z is O or &gt;N—X, where X is H, straight or branched substituted or unsubstituted alkyl, alkenyl or alkynyl, or acyl, carbamoyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, amino, alkyl amino, or dialkyl amino;  
     wherein each of R 1  and R 2  is H or R 1  and R 2  together are ═O;  
     wherein each of R 3  and R 4  is H or R 3  and R 4  together are ═O;  
     wherein each of R 5  and R 6  is, independently, H, alkyl, aralkyl, or aryl;  
     wherein each of R 7  and R 8  is, independently, H or OR 14 , where R 14  is alkyl or —C(O)—R 15 ,  
     where R 15  is H, —CH 2 R 16 , —CHR 16 R 16 , —CR 16 R 17 R 16 , —OR 16 , alkenyl or alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, amino, alkyl amino, or dialkyl amino,  
     wherein each R 16  is straight or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, or amino; and  
     wherein R 17  is straight or branched, unsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, or amino,  
     or wherein R 7  and R 9  together are &gt;O;  
     wherein each of R 9  and R 10  is, independently, H, alkyl, OH, or OR 13 , where R 13  is an alkyl, an acyl, or an amide, or R 9  and R 10  together are ═CH 2 ,  
     or wherein R 8  and R 10  together are &gt;O;  
     wherein if one of R 7  or R 8  and one of R 9  or R 10  is absent, a double bond is formed as indicated by the broken line; and  
     wherein each of R 11  and R 12  is, independently, H, OH, or OR 13 , where R 13  is an alkyl, an acyl, or an amide, or R 11  and R 12  together are ═O,  
     or wherein R 12  and R 10  together are &gt;O, including intermediates in the synthesis.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/340,449, filed Dec. 14, 2001, the contents of whichare hereby incorporated by reference.

[0002] This invention has been made with government support underNational Institutes of Health grant HL-25848. Accordingly, the U.S.Government has certain rights in the invention.

[0003] Throughout this application, various publications are referencedby Roman numeral superscripts. Full citations for these publications maybe found at the end of the specification immediately preceding theclaims. The disclosures of these publications in their entireties arehereby incorporated by reference into this application in order to morefully describe the state of the art as known to those skilled therein asof the date of the invention described and claimed herein.

BACKGROUND OF THE INVENTION

[0004] Neurotrophic factors are functionally defined as molecules whichpromote the maintenance and growth of neurons in vitro and in vivo.¹Among such factors are the nerve growth factor (NGF) and glialcell-derived neurotrophic factor (GDNF). Intraventricular administrationof NGF to rats and primates reduces cholinergic neuronal degeneration,with potential implications for the treatment of Alzheimer'sdisease.^(2a, 3) GDNF may have consequences in the treatment ofParkinson's disease.^(2b) However, optimism along these lines istempered by concerns as to the pharmacokinetics and bioavailability ofpolypeptidal factors.³ It is in this connection that the discovery ofnon-peptidal small molecules with neurotrophic properties is potentiallyof great significance.⁴ It seems appropriate to explore non-peptidalneurotrophic agents in detail as to their biological function and theirusefulness, if any, in the treatment of neurodegenerative diseases. Amastery of the total synthesis of such small-molecule natural productscould be most helpful, not only in improving access to these difficultlyavailable agents, but in providing the basis for probing their SARprofiles.

[0005] Described below is the total synthesis of the pentacyclicsesquiterpene dilactone, merrilactone A (1). This compound hadpreviously been obtained in 0.004% yield from the methanol extract ofthe pericarps of Illicium merrillianum.⁵ Preliminary studies indicatedthat 1 greatly promotes neurite outgrowth in fetal rat cortical neuronsat concentrations as low as 0.1-10 μmol. Further investigations to datehave been hampered by the scarcity of the natural merrilactone A.

SUMMARY OF THE INVENTION

[0006] This invention provides a total synthesis of Merrillactone andMerrilactone analogues having the structure

[0007] wherein Z is O or >N—X, where X is H, straight or branchedsubstituted or unsubstituted alkyl, alkenyl or alkynyl, or acyl,carbamoyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino;

[0008] wherein each of R₁ and R₂ is H or R₁ and R₂ together are ═O;

[0009] wherein each of R₃ and R₄ is H or R₃ and R₄ together are ═O;

[0010] wherein each of R₅ and R₆ is, independently, H, alkyl, aralkyl,or aryl;

[0011] wherein each of R₇ and R₈ is, independently, H or OR₁₄, where R₁₄is alkyl or —C(O)—R₁₅,

[0012] where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆, —CR₁₆R₁₇R₁₆, —OR₁₆, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino,

[0013] wherein each R₁₆ is straight or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, or amino; and

[0014] wherein R₁₇ is straight or branched, unsubstituted alkyl, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, oramino,

[0015] or wherein R₇ and R₉ together are >O;

[0016] wherein each of R₉ and R₁₀ is, independently, H, alkyl, OH, orOR₁₃, where R₁₃ is an alkyl, an acyl, or an amide, or R₉ and R₁₀together are ═CH₂,

[0017] or wherein R₈ and R₁₀ together are >O;

[0018] wherein if one of R₇ or R₈ and one of R₉ or R₁₀ is absent, adouble bond is formed as indicated by the broken line; and

[0019] wherein each of R₁₁ and R₁₂ is, independently, H, OH, or OR₁₃,where R₁₃ is an alkyl, an acyl, or an amide, or R₁₁ and R12 together are═O,

[0020] or wherein R₁₂ and R₁₀ together are >O.

[0021] The invention also provides intermediates for use in thesynthesis.

[0022] The total synthesis of the title compound has been accomplishedin 20 steps. The key step is a free radical cyclization of vinyl bromide29 to afford 30. The synthesis also features an efficient Diels-Alderreaction of 2,3-dimethylmaleic anhydride with1-(tert-butyldimethylsiloxy)-butadiene. The oxetane moiety ofmerrilactone A is fashioned via a Payne-like rearrangement of ahydroxyepoxide (see 2->1).

DETAILED DESCRIPTION OF THE INVENTION

[0023] In one embodiment, this invention provides a compound having thestructure

[0024] wherein Z is O or >N—X, where X is H, straight or branchedsubstituted or unsubstituted alkyl, alkenyl or alkynyl, or acyl,carbamoyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino;

[0025] wherein each of R₁ and R₂ is H or R₁ and R₂ together are ═O;

[0026] wherein each of R₃ and R₄ is H or R₃ and R₄ together are ═O;

[0027] wherein each of R₅ and R₆ is, independently, H, alkyl, aralkyl,or aryl;

[0028] wherein each of R₇ and R₈ is, independently, H or OR₁₄, where R₁₄is alkyl or —C(O)-R₁₅,

[0029] where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆, —CR₁₆R₁₇R₁₆, —OR₁₆, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino,

[0030] wherein each R₁₆ is straight or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, or amino; and

[0031] wherein R₁₇ is straight or branched, unsubstituted alkyl, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, oramino,

[0032] or wherein R7 and R₉ together are >O;

[0033] wherein each of R₉ and R₁₀ is, independently, H, alkyl, OH, orOR₁₃, where R₁₃ is an alkyl, an acyl, or an amide, or R₉ and R₁₀together are ═CH₂,

[0034] or wherein R₈ and R₁₀ together are >O;

[0035] wherein if one of R₇ or R₈ and one of R₉ or R₁₀ is absent, adouble bond is formed as indicated by the broken line; and

[0036] wherein each of R₁₁ and R₁₂ is, independently, H, OH, or OR₁₃,where R₁₃ is an alkyl, an acyl, or an amide, or R₁₁ and R₁₂ together are═O,

[0037] or wherein R₁₂ and R₁₀ together are >O.

[0038] In another embodiment of the compound Z is >N—X, where X is H,straight or branched substituted or unsubstituted alkyl, alkenyl oralkynyl, or acyl, carbamoyl, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, aralkyl, amino, alkyl amino, or dialkyl amino.

[0039] In yet another embodiment of the compound Z is O or >N—X, where Xis H, straight or branched alkyl, alkenyl or alkynyl, or acyl,carbamoyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino;

[0040] wherein each of R₁ and R₂ is H or R₁ and R₂ together are ═O;

[0041] wherein each of R₃ and R₄ is H or R₃ and R₄ together are ═O;

[0042] wherein each of R₅ and R₆ is, independently, H, alkyl, oraralkyl;

[0043] wherein each of R₇ and R₈ is, independently, H or OR₁₄, where R₁₄is alkyl or —C(O)—R₁₅,

[0044] where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆, —CR₁₆R₁₇R₁₆, —OR₁₆,cycloalkyl, aryl, or aralkyl,

[0045] wherein each R₁₆ is alkyl, cycloalkyl, or aryl, aralkyl; and

[0046] wherein R₁₇ is alkyl, cycloalkyl, aryl, or aralkyl,

[0047] or wherein R₇ and R₉ together are >O;

[0048] wherein each of R₉ and R₁₀ is, independently, H, alkyl, OH, orOR₁₃, where R₁₃ is an alkyl, an acyl, or an amide, or R₉ and R₁₀together are ═CH₂, or wherein R₈ and R₁₀ together are >O;

[0049] wherein if one of R₇ or R₈ and one of R₉ or R₁₀ is absent, adouble bond is formed as indicated by the broken line; and

[0050] wherein each of R₁₁ and R₁₂ is, independently, H, OH, or OR₁₃,where R₁₃ is an alkyl, an acyl, or an amide, or R₁₁ and R₁₂ together are═O,

[0051] or wherein R₁₂ and R₁₀ together are >O.

[0052] In another embodiment, the compound hasing the structure

[0053] wherein Z is >O;

[0054] wherein each of R₁ and R₂ is H, or R₁ and R₂ together are ═O;

[0055] wherein each of R₃ and R₄ is H, or R₃ and R₄ together are ═O;

[0056] wherein each of R₅ and R₆ is, independently, H, alkyl, aralkyl,or aryl;

[0057] wherein each of R₇ and R₈ is, independently, H or OR₁₄, where R₁₄is alkyl or —C(O)—R₁₅,

[0058] where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆, —CR₁₆R₁₇R₁₆, —OR₁₆, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino,

[0059] wherein each R₁₆ is straight or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, or amino; and

[0060] wherein R₁₇ is straight or branched, unsubstituted alkyl, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, oramino; and

[0061] wherein R₉ is H, alkyl, OH, or OR₁₃, where R₁₃ is an alkyl, anacyl, or an amide.

[0062] In this embodiment, R₉ may be H, alkyl or OR₁₃, where R₁₃ is analkyl, an acyl, or an amide.

[0063] Also disclosed is a compound wherein R₁ and R₂ together are ═O;

[0064] wherein each of R₃ and R₄ is H;

[0065] wherein each of R₅ and R₆ is, independently, H, alkyl, oraralkyl;

[0066] wherein each of R₇ and R₈ is, independently, H or OR₁₄, where R₁₄is alkyl or —C(O)—R₁₅,

[0067] where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆, —CR₁₆R₁₇R₁₆, —OR₁₆, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino,

[0068] wherein each R₁₆ is straight or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, or amino; and

[0069] wherein R₁₇ is straight or branched, unsubstituted alkyl, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, oramino; and wherein R₉ is alkyl.

[0070] In yet another embodiment, the invention provides a compoundhaving the structure

[0071] wherein Z is O or >N—X, where X is H, straight or branchedsubstituted or unsubstituted alkyl, alkenyl or alkynyl, or acyl,carbamoyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino;

[0072] wherein each of R₁ and R₂ is H or R₁ and R₂ together are ═O;

[0073] wherein each of R₃ and R₄ is H or R₃ and R₄ together are ═O;

[0074] wherein each of R₅ and R₆ is, independently, alkyl, aralkyl, oraryl; and

[0075] where Q is H or a silyl protecting group.

[0076] The compound may have the structure

[0077] The compound may also have the structure

[0078] The compound may further have the structure

[0079] The compound also may have the structure

[0080] In a further embodiment, this invention provides a compoundhaving the structure

[0081] wherein each of Ra, Ra′, Rb, and Rb′ is independently H, alkyl,alkenyl, alkynyl, acyl, or carbamoyl, or either Ra and Rb or Ra′ and Rb′together with the carbons to which they are attached form a substitutedor unsubstituted five or six member ring; and

[0082] wherein each of Rc and Rc′ is, independently, H, OH or OR,wherein R is alkyl, acyl or Q, where Q is a silyl protecting group, orboth Rc and Rc′ together are ═O.

[0083] This invention also provides a process for forming a cyclic ringin the compound so as to produce the compound having the structure

[0084] wherein each of Ra, Ra′, Rb, and Rb′ is independently H, alkyl,alkenyl, alkynyl, acyl, or carbamoyl, or either Ra and Rb or Ra′ and Rb′together with the carbons to which they are attached form a substitutedor unsubstituted five or six member ring; and

[0085] wherein each of Rc and Rc′ is, independently, H, OH or OR,wherein R is alkyl, acyl or Q, where Q is a silyl protecting group, orboth Rc and Rc′ together are ═O,

[0086] comprising treating a compound having the structure

[0087] where M is Br or I,

[0088] with Bu₃SnH or tris-(trimethyl silyl)-silane ((TMS)₃SiH) and afree radical initiator so as to thereby produce the compound.

[0089] The process can produce a compound having the structure

[0090] where Q is a silyl protecting group; and

[0091] where each of R′ and R″ is independently alkyl, alkenyl, alkynyl,acyl, or carbamoyl, or R′ and R″ together form a substituted orunsubstituted five or six member ring,

[0092] by treating a compound having the structure

[0093] where M is Br or I,

[0094] with Bu₃SnH or tris-(trimethyl silyl)-silane ((TMS)₃SiH) and afree radical initiator so as to thereby produce the compound.

[0095] The process may also produce a compound having the structure

[0096] by treating a compound having the structure

[0097] where Q is a silyl protecting group; and

[0098] where M is Br or I,

[0099] with Bu₃SnH or tris-(trimethyl silyl)-silane ((TMS)₃SiH) and afree radical initiator so as to thereby produce the compound.

[0100] Furthermore, the process can produce a compound having thestructure

[0101] by treating a compound having the structure

[0102] with Bu₃SnH and AlBN so as to thereby produce the compound.

[0103] This invention also provides a process for synthesizing acompound having the structure

[0104] comprising

[0105] a) reacting a compound having the structure

[0106] where Q is a silyl protecting group,

[0107] with a compound having the structure

[0108] at a temperature of from about 140° C. to 230° C. to produce acompound having the structure

[0109] b) reacting the compound of step a) with MeONa to produce

[0110] c) treating both products of step b) with ClCO₂Me to produce

[0111] d) treating both products, of step c) with NaBH₄ to produce

[0112] e) treating the products of step d) with LiOH to produce

[0113] f) treating the product of step e) with O₃ followed by Bn₂NH*TFAto produce

[0114] g) treating the product of step f) with NaBH₄ to produce

[0115] h) treating the product of step g) with MeC(OEt)₃ to produce

[0116] i) treating the product of step h) LiOH and 12 and to produce

[0117] j) treating the product of step i) with allylSnBu₃ to produce

[0118] k) treating the product of step j) with LHMDS, TMSCl and PhSeCl,and then with PhSeBr and MeCN to produce

[0119] l) treating the product of step k) with O₃, CH₂Cl₂ and 1-hexeneto produce

[0120] m) treating the product of step l) with Bu₃SnH and AlBN toproduce

[0121] n) treating the product of step m) with TsOH to produce

[0122] o) treating the product of step n) with mCPBA or adimethyldioxirane to produce

[0123] p) treating the product of step o) with an acid to produce thecompound.

[0124] The process can also synthesize a compound having the structure

[0125] comprising

[0126] a) reacting a compound having the structure

[0127] with a compound having the structure

[0128] at a temperature of from about 160° C. to 180° C. to produce acompound having the structure

[0129] b) reacting the compound of step a) with MeONa and MeOH toproduce

[0130] c) treating both products of step b) with ClCO₂Me in THF toproduce

[0131] d) treating both products of step c) with NaBH₄ and MeOH toproduce

[0132] e) treating the products of step d) with aqueous LiOH to produce

[0133] f) treating the product of step e) first with 03 and PPh₃, andthen with Bn₂NH*TFA in benzene to produce

[0134] g) treating the product of step f) with NaBH₄ and CH₂Cl₂ in MeOHto produce

[0135] h) treating the product of step g) with MeC(OEt)₃ and PivOH toproduce

[0136] i) treating the product of step h) first with aqueous LiOH andMeOH, and then with 12 and NaHCO₃ in THF to produce

[0137] j) treating the product of step i) with allylSnBu₃, A1BN and PhHto produce

[0138] k) treating the product of step j) first with LHMDS, TMSCI andPhSeCl, and then with PhSeBr and MeCN to produce

[0139] l) treating the product of step k) first with 03, CH₂Cl₂ and1-hexene, and then with PhH, NEt₃ under reflux conditions to produce

[0140] m) treating the product of step 1) with Bu₃SnH and AlBN, and PhHto produce

[0141] n) treating the product of step m) with aqueous TsOH and PhHunder reflux conditions to produce

[0142] o) treating the product of step n) with mCPBA and CH₂Cl₂ toproduce

[0143] p) treating the product of step o) with aqueous TsOH and CH₂Cl₂to produce the compound.

[0144] The abbreviations used are defined below:

[0145] TFA=trifluoroacetic acid

[0146] THF=tetrahydrofuran

[0147] Bn₂NH.TFA=dibenzylammonium trifluoroacetate

[0148] LHMDS=lithium hexamethyldisilazide

[0149] TBS=tert-butyldimethylsilyl

[0150] PivOH=pivalic acid

[0151] AlBN=azobis-(isobutyronitrile)

[0152] PhH=benzene

[0153] MeCN=acetonitrile

[0154] MeOH methanol

[0155] mCPBA=meta-chloroperbenzoic acid

[0156] TsOH=para-toluenesulfonic acid

[0157] The invention further contemplates the use of prodrugs which areconverted in vivo to the therapeutic compounds of the invention (see,e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design andDrug Action”, Academic Press, Chapter 8, the entire contents of whichare hereby incorporated by reference). Such prodrugs can be used toalter the biodistribution (e.g., to allow compounds which would nottypically enter the reactive site of the protease) or thepharmacokinetics of the therapeutic compound.

[0158] Certain embodiments of the disclosed compounds can contain abasic functional group, such as amino or alkylamino, and are thuscapable of forming pharmaceutically acceptable salts withpharmaceutically acceptable acids, or contain an acidic functional groupand are thus capable of forming pharmaceutically acceptable salts withbases. The term “pharmaceutically acceptable salts” in this respect,refers to the relatively non-toxic, inorganic and organic acid or baseaddition salts of compounds of the present invention. These salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound of the invention in its free base or free acid form with asuitable organic or inorganic acid or base, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19).

[0159] It will be noted that the structure of some of the compounds ofthis invention includes asymmetric carbon atoms and thus occur asracemates and racemic mixtures, single enantiomers, diastereomericmixtures and individual diastereomers. All such isomeric forms of thesecompounds are expressly included in this invention. Each stereogeniccarbon may be of the R or S configuration. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of thisinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and/or bystereochemically controlled synthesis.

[0160] Compounds discussed above, such a merrilactone A, promote themaintenance and growth of neurons both in vivo and in vitro and promoteneurite outgrowth in fetal rat cortical neurons. Based on their chemicaland structural similarities to merrilactone A, such activity of thedisclosed compounds is not expected. Furthermore, the activity of thedisclosed compounds both in vivo and in vitro can be determined by usingpublished test procedures.

EXAMPLES AND DISCUSSION Example 1

[0161] The challenge of creating the densely oxygenated, highly compactarchitecture of merrilactone A in the laboratory added to theattractiveness of the project. One of the provocative features of thetarget system is the presence of an oxetane linkage bridging the β-facesof C7 and C1. We envisioned the possibility that such an oxetane mightarise by Payne-like rearrangement of α-epoxide 2. It was furtherconjectured that isomerization of exo-olefin 3 followed by epoxidationwould lead to 2. A critical step en route to 3 might be a free radicalcyclization⁶ of a substrate of type 4, enabling formation of a newquaternary center in a densely substituted environment. It was furtheranticipated that suitable two-fold oxidation of 5 might provide therequired complementary functionality of 4. This line of reasoninginvited a proposal that overall “allyl-lactonization” could be used toconvert 6 to 5. Recognition of the γ,δ-unsaturated acid character of 6called to mind the possibility of reaching this intermediate by Claisenrearrangement via 7. Preparation of 7 was to be achieved through a ringcleavage-reclosure sequence from 8. The latter structure, in turn, wassuggestive of a Diels-Alder based construction. However, the prospectsof a direct cycloaddition between 9 and 10 to reach 8 were notpromising. Even uncongested butenolides are not particularly powerfuldienophiles. The presence of the two methyl groups, creating atetrasubstituted “dienophilic” double bond, was likely to preclude sucha cycloaddition. Hence, we sought to compensate for the expected stericimpediment through recourse to a more reactive dienophile substructure(cf. 12). The development of a scheme which, in effect, circumvents theinertness of 10 was a key challenge to our prospectus.

[0162] The reaction of 2,3-dimethylmaleic anhydride (12)⁷ and 11⁸occurred under the conditions shown, to afford 13 in 74% yield. We nextturned to regioselective reduction of the C14 carbonyl group (futuremerrilactone A numbering). Attempted reductions with conventionalborohydride reagents led to complex mixtures. This lack of selectivitynecessitated a somewhat awkward, but high yielding, circumvention. Itwas established that ring opening of 13 with sodium methoxide proceededsmoothly. Treatment of the resulting salts (14 and 15) with ClCO₂Me inTHF afforded mixed anhydrides 16 and 17. Remarkably, exposure of thismixture to the action of NaBH₄ and methanol⁹ led to clean reduction of17 while leaving 16 unchanged. (The inertness of the C12 carbonyl in 16may be due to its axial orientation.) Subsequent addition of lithiumhydroxide to the mixture afforded compounds 18 and 20, easily separableby a simple extraction. Treatment of 18 with LiBHEt₃ ¹¹ also afforded20. The regioconvergence of this scheme obviated any need forchromatographic separation of intermediates and afforded 20 in 78%overall yield from 13.

[0163] The stage was now set for the ring cleavage-reclosure sequence(cf. 8→7 in retrosynthesis plan). Ozonolysis of 20 followed by reductiveworkup, as shown, led to a dialdehyde, which on aldol condensation usingCorey's conditions¹² afforded the cyclodehydrated product 21 in highyield. Following reduction¹³ of the aldehyde function, allylic alcohol22 was in hand. The next stage called for Claisen rearrangement to reach23. The most advantageous way to achieve this result proved to be viathe Johnson orthoester protocol.¹⁴ The mixture of esters (23/24˜1.8:1)thus produced was hydrolyzed, and the resultant acids subjected toiodolactonization. Two crystalline and chromatographically separableiodolactones, 25 and 26, were obtained in 35 and 59% yields,respectively. Chain extension of the required “anti-backbone” isomer 26was accomplished (75% yield) by the elegant C-allylation method ofKeck.¹⁵

[0164] As noted above, (cf. 5→4 in the retrosynthesis) oxidation at twosites would be required to complete the setting for the proposed keycyclization step (cf. 4→3). An efficient sequence to deal withpotentially awkward functional group management issues in advancingbeyond 27 was developed. Thus, selenenylation at C10 was accomplishedvia an intermediate silyl ketene acetal. With this subgoal achieved,bromoselenenylation of the terminal vinyl group of 27 was conductedaccording to methodology introduced some years ago by Rauscher.¹⁶Concurrent oxidative deselenation afforded the desired 29. The settingfor testing the key free radical cyclization was at hand. Our initialconcerns that the steric congestion at the sp² center at C9 might leadto the competitive reduction of the vinylic radical, fortunately, provedgroundless. In the event, treatment of 29 under the standardconditions^(6a) afforded a 90% yield of 30.

[0165] Isomerization of the exo methylene group in 30 envisioned at theplanning stage was accomplished concurrently with liberation of the C7β-alcohol. While hydroxyl groups have often been used to directepoxidation with peracids in a syn sense,¹⁷ in the case at hand thecongested nature of the β-face of the C1-C2 double bond is such thatepoxidation occurs primarily (3.5:1) from its α-face (see compound 2).¹⁸In the final step of the synthesis, merrilactone A is produced by anacid-induced homo-Payne rearrangement (see 2→1). The spectroscopicproperties of 31, 2, and 1 were in complete accord with the publisheddata.^(5b) Further confirmation came from the identity of the NMRspectra of synthetic (±)-1 with those of natural merrilactone A.

[0166] In summary, a total synthesis of merrilactone A has beenaccomplished. The first generation route described above provides, forthe first time, ample material for extensive preclinical evaluations ofmerrilactone A. The chemistry developed to date (20 steps, 10.7% overallyield) is amenable to scale-up to multigram levels. Moreover, the use ofdimethylmaleic anhydride (12) as a dienophile leading to theincorporation of two angular methyl groups has broad potentialimplications which warrant follow-up.

[0167] Experimental Details for Example 1

[0168] All reactions were carried out under an argon atmosphere.Tetrahydrofuran, diethyl ether, and dichloromethane were purified bypassing through solvent columns.10 Other solvents were obtainedcommercially and were used as received.1-(t-butyldimethylsilyloxy)-1,3-butadiene was prepared according to aliterature procedure. All other reagents were reagent grade and purifiedwhere necessary. Reactions were monitored by thin layer chromatography(TLC) using EM Science 60F silica gel plates. Flash columnchromatography was performed over Scientific Adsorbents Inc. silica gel(32-63 μm). Melting points were measured on a Thomas Hoover capillarymelting point apparatus and are uncorrected. ¹H NMR and ¹³C NMR spectrawere recorded on Bruker-Spectrospin spectrometers. The chemical shiftsare reported as δ values (ppm) relative to TMS. Infrared spectra wererecorded on a Perkin-Elmer Paragon 1000 FT-IR Spectrophotometer (NaClplates, film). Low-Resolution mass spectral analyses were performed on aJeol LC/MS system using chemical ionization.

[0169] Diels-Alder Adduct 13. A flask containing a mixture of2,3-dimethylmaleic anhydride (2.520 g, 20.0 mmol),1-(t-butyldimethylsilyloxy)-1,3-butadiene (5.53 g, 30.0 mmol),symm-collidine (150 mg), Methylene Blue (5 mg), and mesitylene (6.2 mL)was purged with argon several times and stirred under reflux in an oilbath at 165° C. for 2.5 days. The solvents were removed by Kugelrohrdistillation at 100° C., and the residue was purified by flashchromatography (hexanes/EtOAc 19:1) to afford 4.604 g (74% yield) of theproduct which crystallized upon standing. ¹H NMR (CDCl₃, 400 MHz):6-0.03 (s, 3H), 0.01 (s, 3H), 0.79 (s, 9H), 1.16 (s, 3H), 1.31 (s, 3H),2.00 (dd, J=21, J=4, 1H), 2.99 (d, J=21, 1H), 4.13 (d, J=5.7, 1H), 5.96(m, 2H); ¹³C NMR (CDCl₃, 100 MHz): −5.6, −4.4, 14.7, 17.7, 25.3, 25.6,30.0, 44.2, 53.9, 70.2, 126.9, 130.1, 175.4, 176.7; IR (NaCl, cm⁻¹):1784 s, 1852 m (anhydride C═O); MS Found: 311.1 (M+1), Calc. 310.16; Mp62-63° C.

[0170] Lactone 20. Part A. A stirring mixture of Diels-Alder Adduct 13(1.240 g, 4.00 mmol) and dry methanol (10 mL) was treated at RT with 25%methanolic solution of MeONa (0.92 mL, 4.02 mmol). After 15 minutes, themixture was rotary evaporated, and the residue was coevaporated twicewith benzene to dryness. The resulting viscous oil was dissolved in THF(10 mL), the solution was cooled in an ice bath and treated with ClCO₂Me(0.400 mL, 5.18 mmol). After 20 minutes, the mixture was cooled to −78°C., and solid NaBH₄ (400 mg, 10.57 mmol) was added, followed by dropwiseaddition of dry MeOH (1.60 mL). The mixture was allowed to warm up to−35° C., quenched with saturated aqueous ammonium chloride (6 mL),warmed to RT, diluted with water, and extracted twice with Et₂O. Theaqueous phase was acidified to pH 3-4 with 1 M HCl and extracted twicewith Et₂O. The combined ethereal extract was evaporated, the residuedissolved in THF (12 mL), and stirred vigorously with aqueous LiOH (4mL, 5%) for 1.5 hours. The mixture was diluted with water and extracted3 times with hexanes. The hexane extract (containing almost pure lactone20) was washed twice with 1 M NaOH, then brine, dried with Na₂SO₄, andset aside.

[0171] Part B. The combined alkaline aqueous phase from the previousstep was acidified with 1 M HCl and extracted 3 times with Et₂O. Theethereal solution was dried over MgSO₄, rotary evaporated, and theresidue was coevaporated with benzene. The resulting crude half-ester 18(758 mg, 2.21 mmol) was cooled in an ice bath and treated with LiBHEt₃(1M in THF, 12 mL). After stirring overnight at RT, the mixture wascooled again in an ice bath, quenched with 1 M NaOH (8 mL), and thencarefully treated with 10% H₂O₂ (18 mL) added in several portions toavoid excessive heating. After stirring for 0.5 hour, the solution wasacidified with 1 M HCl to pH 5-6 and extracted with Et₂O twice. Theviscous residue on the bottom of the flask was shaken vigorously with 1M HCl and Et₂O until completely dissolved. The resulting two-phasemixture was combined with the aqueous phase, acidified to pH 5-6 again,and extracted with ether twice. The combined ethereal extract was washedwith brine once, dried over MgSO₄, rotary evaporated, redissolved in 10mL of CH₂Cl₂, and treated with TFA (0.04 mL). After 3 days, this mixturewas combined with the previously obtained hexane solution of lactone 20,evaporated, and subjected to flash chromatography (hexanes/EtOAc 19:1)to afford 925 mg (78% yield) of the product as colorless oil whichcrystallized upon standing. ¹H NMR (CDCl₃, 500 MHz): δ 0.05 (s, 3H),0.08 (s, 3H), 0.86 (s, 9H), 1.06 (s, 3H), 1.09 (s, 3H), 2.00 (ddd,J=19.3, J=1.9, J=1.0, 1H), 2.14 (ddd, J=19.3, J=2.1, J=1.6, 1H), 3.73(d, J=7.6, 1H), 3.97 (d, J=4.7, 1H), 4.32 (d, J=7.6, 1H), 5.76-5.83 (m,2H); ¹³C NMR (CDCl₃, 100 MHz): −5.4, −4.1, 16.2, 17.7, 25.6, 26.2, 30.7,39.2, 50.1, 70.0, 75.4, 126.4, 126.7, 179.6; IR (NaCl, cm⁻¹): 1777 s(C═O); MS Found: 297.1 (M+1), Calc. 296.18; Mp 44-44.5° C.

[0172] Unsaturated aldehyde 21. A solution of lactone 20 (592 mg, 2mmol) in a mixture of dry CH₂Cl₂ (20 mL) and dry MeOH (20 mL) wasozonated at −78° C. until blue color appeared, then purged with oxygenuntil colorless, treated with PPh₃ (630 mg, 2.4 mmol, added in 6 mL ofCH₂Cl₂), and allowed to warm up to RT. The solvents were removed byrotary evaporation, the residue was coevaporated with benzene anddissolved in benzene (40 mL). Dibenzylammonium trifluoroacetate (124 mg,0.4 mmol) was added, and the resulting solution was stirred at 63° C.for 9 hours. The solvent was evaporated, and the residue waschromatographed (hexanes/ethyl acetate 9:1) to afford 580 mg (94% yield)of the product as colorless oil which crystallized upon standing. ¹H NMR(CDCl₃, 400 MHz): δ 0.12 (s, 3H), 0.15 (s, 3H), 0.90 (s, 9H), 1.25 (s,3H), 1.33 (s, 3H), 4.04 (d, J=9.2, 1H), 4.26 (d, J=9.2, 1H), 4.61 (d,J=2.2, 1H), 6.62 (d, J=2.2, 1H), 9.82 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz):−5.1, −4.7, 16.3, 17.5, 18.0, 25.6, 53.2, 57.4, 75.8, 82.9, 132.9,149.3, 149.6, 176.1, 189.8; IR (NaCl, cm⁻¹): 1688 s (aldehyde C═O), 1778s (lactone C═O); MS Found: 311.1 (M+1), Calc. 310.16; Mp 57-57.5° C.

[0173] Allylic alcohol 22. Solid NaBH₄ (130 mg, 3.44 mmol) was added toa solution of aldehyde 21 (536 mg, 1.73 mmol) in CH₂Cl₂ (28 mL) stirringat −78° C., followed by slow addition of methanol (12 mL). The mixturewas allowed to warm slowly to RT and then quenched by careful additionof saturated aqueous NH₄Cl (5 mL), then diluted with water, andextracted 3 times with CH₂Cl₂. The organic extract was washed once withbrine, dried over Na₂SO₄ and rotary evaporated. The resulting colorlessoil contained 1% of CH₂Cl₂ by ¹H NMR, but otherwise was completely pure(593 mg, quant. yield). The oil crystallized after prolonged standing.¹H NMR (CDCl₃, D₂O, 500 MHz): δ 0.07 (s, 3H), 0.09 (s, 3H), 0.87 (s,9H), 1.16 (s, 3H), 1.18 (s, 3H), 4.03 (d, J=8.7, 1H), 4.15 (d, J=14.0,1H), 4.21 (d, J=8.7, 1H), 4.28 (d, J=14.0, 1H), 4.30 (d, J=0.8, 1H),5.59 (d, J=0.8, 1H); ¹³C NMR (CDCl₃, 100 MHz): −5.1, −4.6, 16.3, 17.4,18.0, 25.7, 54.6, 58.7, 59.5, 78.9, 83.1, 126.2, 150.6, 177.3; IR (NaCl,cm⁻¹): 1757 s (C═O), 3436 br (O—H); MS Found: 313.1 (M+1), Calc. 312.18;Mp 71.5-72.5° C.

[0174] Claisen Esters 23 and 24. A mixture of allylic alcohol 22 (593mg, 1.87 mmol), pivalic acid (75 mg, 0.74 mmol), freshly distilledtriethyl orthoacetate (5.5 mL, 30 mmol), and mesitylene (5.5 mL) wasstirred in an oil bath at 135-140° C. in a flask equipped with ashort-path distillation head under a slow flow of argon, adding 75 mg ofpivalic acid every 2 hours and monitoring the progress of the reactionby ¹H NMR. After 12 hrs, 2 mL of triethyl orthoacetate was added and theheating was continued overnight. NMR analysis indicated ca. 95%conversion. The mixture was cooled to RT, the solvents were removed byKugelrohr distillation at 100° C., and the residue was purified by flashchromatography (hexanes/EtOAc 14:1) to afford 658 mg (92% yield) of theproduct as a mixture of diastereomers (23/24=1.8:1). ¹H NMR (CDCl₃, 400MHz): δ −0.03 (s, 1.65H), 0.08 (app s, 4.65H), 0.11 (s, 3H), 0.86 (s,4.95H), 0.88 (s, 9H), 1.18 (s, 3H), 1.19 (s, 3H), 1.23-1.30 (m, 7.95H),2.46 (dd, J=15.8, J=7.4, 1H), 2.53 (m, 1.1H), 2.58 (dd, J=15.8, J 6.5,1H), 3.05 (m, 1H), 3.24 (m, 0.55H), 3.88 (d, J=8.7, 1H), 3.90 (d, J=4.1,1H), 3.94 (d, J=8.2, 0.55H), 4.13-4.19 (m, 5.2H), 4.85 (d, J=3, 0.55H),4.91 (d, J=3, 0.55H), 5.00 (d, J=2.2, 1H), 5.03 (d, J=2.2, 1H); IR(NaCl, cm⁻¹): 1736 s (ester C═O), 1777 s (lactone C═O); MS Found: 383.2(M+1),Calc. 382.22.

[0175] Iodolactones 25 and 26. Part A: Hydrolysis. The diastereomericmixture of esters 23 and 24 (569 mg, 1.49 mmol) was stirred with asolution of LiOH (200 mg) in a mixture of MeOH (6 mL) and water (2 mL)at RT for 12 hrs, diluted with water, acidified with 1 M HCl to pH 2-3,and extracted 3 times with CH₂Cl₂. The organic extract was washed withbrine, dried over Na₂SO₄, and rotary evaporated. The residue (ca. 0.55g) was used directly in the next step. ¹H NMR (CDCl₃, 400 MHz): δ 0.01(s, 1.65H), 0.08 (s, 3H), 0.09 (s, 1.65H), 0.11 (s, 3H), 0.87 (s,4.95H), 0.89 (s, 9H), 1.18 (s, 3H), 1.20 (s, 3H), 1.23 (s, 1.65H), 1.25(s, 1.65H), 2.53 (dd, J=16.2, J=7.3, 1H), 2.61 (m, obscured by 2.64 dd,1.1H), 2.64 (dd, J=16.2, J=6.6, 1H), 3.06 (m, 1H), 3.23 (m, 0.55H), 3.88(d, J 4.0, 1H), 3.89 (d, J=8.6, 1H), 3.95 (d, J 8.2, 0.55H), 4.15 (d,J=8.2, 0.55H), 4.16 (d, obscured by 4.19 d, 0.55H), 4.19 (d, J=8.6, 1H),4.90 (d, J=2.9, 0.55H), 4.95 (d, J=2.9, 0.55H), 5.04 (d, J=2.2, 1H),5.06 (d, J=2.2, 1H), COOH not observed; IR (NaCl, cm⁻¹): 1711 s (acidC═O), 1774 s, br (lactone C═O), 3000-3500 br (COO—H); MS Found: 355.1(M+1), Calc. 354.19.

[0176] Part B: Iodolactonization. To a solution of the mixture ofcarboxylic acids 23a and 23b (0.55 g, see above) in 3 mL of THF, wasadded 7.5 mL of saturated aqueous NaHCO₃. The mixture was cooled in anice bath, treated with a solution of I₂ (1.143 g, 4.5 mmol) in 12 mL ofTHF, protected from light, and stirred at RT for 12 hrs. Excess I₂ wasquenched by addition of aqueous Na₂SO₃, the mixture was diluted withwater and extracted 3 times with CH₂Cl₂. The organic extract was washedwith brine, dried over Na₂SO₄, and rotary evaporated. The mixture ofproducts crystallized spontaneously. The crude product was taken up inCH₂Cl₂ and preadsorbed on silica gel. Column chromatography(hexanes/EtOAc 7:1, then 3:1) gave incomplete separation. The mixedfractions were chromatographed again. Combined yield of the desirediodolactone 26 was 421 mg (59% based on the ester mixture).Additionally, 250 mg of the epimeric iodolactone 25 (35% yield) wasobtained. 26 (major iodolactone): ¹H NMR (CDCl₃, 400 MHz): δ 0.08 (apps, 6H), 0.89 (s, 9H), 1.17 (s, 3H), 1.24 (s, 3H), 2.45 (dd, J=19.3,J=2.4, 1H), 2.79 (dd, J=11.5, J=2.4, 1H), 3.33 (d, J=11.1, 1H), 3.36(dd, partly obscured by 3.33 d, J=19.3, J=11.5, 1H), 3.57 (d, J=11.1,1H), 3.82 (s, 1H), 3.89 (d, J=8.4, 1H), 4.31 (d, J=8.4, 1H); ¹³C NMR(CDCl₃, 100 MHz): −5.3, −4.9, 7.8, 15.8, 16.2, 17.7, 25.6, 37.3, 55.9,57.1, 61.2, 72.4, 87.9, 95.5, 174.1, 176.3; IR (NaCl, cm⁻¹): 1777 s(C═O); MS Found: 481.0 (M+1), Calc. 480.08; Mp 213-214° C. 25 (minoriodolactone): ¹H NMR (CDCl₃, 400 MHz): δ 0.06 (s, 3H), 0.10 (s, 3H),0.91 (s, 9H), 1.20 (s, 3H), 1.23 (s, 3H), 2.78-2.89 (m, 2H), 3.06 (m,1H), 3.25 (d, J=11.1, 1H), 3.73 (d, J=11.1, 1H), 3.85 (d, J=9.4, 1H),4.00 (d, J=7.2, 1H), 4.27 (d, J=9.4, 1H); ¹³C NMR (CDCl₃, 100 MHz):−5.0, −4.5, 14.5, 15.7, 17.2, 17.8, 25.7, 30.9, 50.0, 55.9, 61.3, 73.7,78.3, 93.4, 175.4, 176.0; IR (NaCl, cm⁻¹): 1774 s (C═O); MS Found: 481.0(M+1), Calc. 480.08; Mp 216-217° C.

[0177] Keck Product 27. Iodolactone 26 (421 mg, 0.876 mmol),allyltributyltin (1.36 mL, 4.39 mmol), AIBN (14 mg, 0.085 mmol), andbenzene (4.4 mL) were added into a flask equipped with a refluxcondenser and a magnetic stirring bar, the mixture was degassed usingthe freeze-pump-thaw technique (3-4 cycles) and immersed into an oilbath kept at 85° C. After 3 hours, another 14 mg of AIBN was added, andthe heating was continued for an additional 1.5 hours. The mixture wascooled, the solvent was rotary evaporated, and the residue was dilutedwith 1 mL of CH₂Cl₂ (to prevent crystallization) and chromatographed(hexanes/EtOAc 7:1) to afford the crystalline product contaminated withBu₃SnBr. The impurities were removed by washing the crystals withhexanes, evaporating the washings, and washing the crystalline residuewith hexanes again, and so on until evaporation gave mostly oil. Thepure product thus obtained weighed 258 mg (75% yield). ¹H NMR (CDCl₃,500 MHz): δ 0.06 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.17 (s, 3H), 1.23(s, 3H), 1.56 (m, 1H), 1.98 (m, 1H), 2.05 (m, 1H), 2.17 (m, 1H), 2.54(dd, J=8.8, J=1.5, 1H), 2.71 (d, J=10.9, 1H), 3.00 (dd, J=18.8, J=10.9,1H), 3.78 (s, 1H), 3.87 (d, J 8.6, 1H), 4.21 (d, J 8.6, 1H), 5.05 (d,J=10.2, 1H), 5.10 (dd, J 17.2, J=1.2, 1H), 5.77 (d, J=10.3, 1H), 5.80(m, 1H); ¹³C NMR (CDCl₃, 100 MHz): −5.2, −4.8, 16.2, 16.4, 17.8, 25.6,27.7, 33.9, 36.5, 54.0, 58.0, 60.3, 72.5, 89.0, 98.3, 116.1, 136.5,174.6, 176.6; IR (NaCl, Cm⁻¹): 1779 s (C═O); MS Found: 395.2 (M+1),Calc. 394.22; Mp 154-155° C.

[0178] Cyclization Precursor 29. To a solution of 27 (258 mg, 0.654mmol) in 12 mL of THF stirring at −78° C. was added LHMDS (1 M in THF,0.75 mL). After 0.5 hour, TMSC1 (100 μL, 0.788 mmol) was added. Themixture was stirred for 0.5 hour at −78° C., then for 0.5 hour at RT,cooled to −78° C. and treated with PhSeCl (142 mg, 0.741 mmol) in 9 mLof THF. The mixture was allowed to warm to RT over 1.5 hours, dilutedwith water, and extracted with Et₂O 3 times. The ethereal extract wasdried over MgSO₄, rotary evaporated, the residue was diluted withCH₂Cl₂, and evaporated again. The crude selenide was dissolved in 7 mLof dry MeCN and treated with a solution of PhSeBr until brownish colorpersisted (ca. 6 mL of solution prepared from 119 mg of (PhSe)₂, 0.38 mLof 2M Br₂ in CHCl₃, and 6.6 mL of MeCN) at RT. After 0.5 hour, themixture was evaporated at 25° C. by stirring under vacuum, the residueredissolved in 20 ml of CH₂Cl₂, and ozonated at −78° C. until blue colorpersisted. The cold mixture was treated with 3 mL of 1-hexene and thenadded in several portions to a boiling solution of 2 mL of NEt₃ in 80 mLof benzene. After the addition was complete, the mixture was refluxedfor 0.5 hour, evaporated to dryness, and the residue was chromatographed(hexanes/EtOAc 4:1) to afford 237 mg (77% yield) of the whitecrystalline product. ¹H NMR (CDCl₃, 400 MHz): δ 0.17(s, 3H), 0.19 (s,3H), 0.90 (s, 9H), 0.91 (s, 3H), 1.20 (s, 3H), 2.18-2.26 (m, 1H),2.32-2.49 (m, 3H), 3.93 (d, J=10.2, 1H), 4.36 (s, 1H), 4.68 (d, J=10.2,1H), 5.42 (d, J 2.0, 1H), 5.57 (dd, J=1.0, J=0.8, 1H), 5.93 (s, 1H); ¹³CNMR (CDCl₃, 100 MHz): −5.2, −5.0, 16.2, 18.4, 25.8, 32.4, 35.5, 49.7,59.7, 71.7, 73.9, 94.7, 114.3, 117.4, 132.1, 171.4, 171.9, 175.6; IR(NaCl, cm⁻¹): 1765 s (C═O); MS Found: 471.0 (M+1), Calc. 470.11; Mp145-146.5° C.

[0179] Exo Olefin 30. A solution of 29 (237 mg, 0.492 mmol), Bu₃SnH (270μL, 0.985 mmol), and AIBN (8 mg, 0.049 mmol) in 50 mL of benzene wasdegassed using the freeze-pump-thaw technique (3 cycles) and heatedunder reflux in an oil bath at 85° C. After 2.5 hrs, 8 mg of AIBN wasadded and the heating was continued for 1.5 hrs. The mixture wasevaporated, and the residue was chromatographed (hexanes/EtOAc 7:1) toafford 185 mg of the white crystalline product still containingtributyltin impurities. The latter were removed by washing the crystalswith hexanes (3×3 mL), evaporating the washings, and washing thecrystalline residue with hexanes again, and so on until evaporation gavemostly oil. The product thus obtained was pure by ¹H NMR and weighed 177mg (90% yield). ¹H NMR (CDCl₃, 400 MHz): δ 0.01(s, 3H), 0.06 (s, 3H),0.86 (s, 9H), 1.22 (s, 3H), 1.24 (s, 3H), 1.76 (m, 1H), 2.14 (m, 1H),2.61 (m, 2H), 2.79 (d, J=19.2, 1H), 3.03 (d, J=19.2, 1H), 3.89 (d,J=8.4, 1H), 4.01 (s, 1H), 4.43 (d, J=8.4, 1H), 4.95 (app s, 1H), 5.25(dd, J=1.9, J=1.7, 1H); ¹³C NMR (CDCl₃, 100 MHz): −4.4, −3.4, 16.7,17.7, 17.9, 25.8, 33.8, 37.6, 43.6, 56.8, 62.5, 66.3, 72.4, 89.2, 106.2,112.2, 152.9, 174.5, 177.0; IR (NaCl, cm⁻¹): 1778 s (C═O); MS Found:393.1 (M+1), Calc. 392.20; Mp 175-175.5° C.

[0180] Alcohol 31. A mixture of 30 (177 mg, 0.451 mmol), TsOH—H₂O (343mg, 1.80 mmol), and benzene (17 mL) was heated under reflux for 3 hoursin an oil bath at 90° C., then cooled, diluted with Et₂O, and washedwith aqueous NaHCO₃. The aqueous wash was extracted with CH₂Cl₂ 3 times,the combined organic phase was dried over Na₂SO₄, rotary evaporated, andchromatographed (CH₂Cl₂/EtOAc 5:1) to afford 123 mg (98%) of theproduct. ¹H NMR (CDCl₃, 300 MHz): δ 1.19 (s, 3H), 1.23 (s, 3H), 1.82 (d,J=1.5, 3H), 1.82 (m, 2H), 2.66 (d, J=19.1, 1H), 2.85 (d, J=19.1, 1H),3.75 (d, J=6.0, 1H), 3.95 (d, J=8.7, 1H), 4.16 (d, J=6.0, 1H), 4.22 (d,J 8.7, 1H), 5.37 (m, J 1.5, 1H), ¹³C NMR (CDCl₃, 75 MHz): 15.0, 15.7,16.7, 39.9, 41.0, 55.5, 62.5, 69.8, 73.8, 86.3, 104.6, 124.6, 141.5,175.4, 179.0; ¹H NMR (CD₃OD, 400 MHz): 1.15 (s, 3H), 1.19 (d, J=0.8,3H), 1.79 (ddd, J=2.4, J=2.1, J=1.5, 3H), 2.35 (ddq, J=18.4, J=2.4,J=2.4, 1H), 2.55 (ddq, J=18.4, J=2.1, J=2.1, 1H), 2.77 (d, J=19.3, 1H),2.87 (d, J=19.3, 1H), 3.97 (d, J=8.6, 1H), 4.08 (s, 1H), 4.16 (d, J=8.6,J=0.8, 1H), 5.33 (ddq, J=2.4, J=2.1, J=1.5, 1H); 6 ¹³C NMR (CD₃OD, 100MHz): 15.1, 16.1, 16.9, 40.6, 41.9, 57.0, 64.0, 71.5, 74.4, 87.1, 106.5,125.1, 143.8, 177.9, 180.2; IR (NaCl, cm⁻¹): 1770 s (C═O), 3462 br(O—H); MS Found: 279.1 (M+1), Calc. 278.12; Mp 189-190° C. (softens at175° C).

[0181] Our ¹H and ¹³C NMR data for spectra recorded in CD₃OD match thosereported by Fukuyama et al.^(5b) for CDCl₃ (probably due to atypographical error).

[0182] Epoxides 2 and 2a. The procedure of Fukuyama et al.^(5b) wasessentially followed. A solution of alcohol 30 (123 mg, 0.442 mmol) andmCPBA (180 mg, 1.04 mmol) in 12 ml of CH₂Cl₂ was left for 2 days at RT.The mixture was treated with saturated aqueous Na₂SO₃ and aqueousNaHCO₃, and extracted 3 times with CH₂Cl₂. The extract was washed withbrine, dried over Na₂SO₄, and rotary evaporated. The crude product (133mg, quant.) consisted of a 3.5:1 mixture of epoxides 2 and 2a. Themixture was used directly in the next step, since column chromatography(CHCl₃/MeOH^(5b) or CH₂Cl₂/AcOEt) did not result in efficient separationof the epimers. The pure major epoxide 2 could be obtained by tworecrystallizations from EtOAc/hexanes. Major epoxide 2: ¹H NMR (CD₃OD,400 MHz): δ 1.11 (s, 3H), 1.16 (s, 3H), 1.54 (s, 3H), 2.07 (d, J=16.2,1H), 2.25 (dd, J=16.2, J=1.6, 1H), 2.58 (d, J=19.1, 1H), 3.00 (d,J=19.1, 1H), 3.66 (d, J=1.6, 1H), 3.93 (d, J=8.5, 1H), 4.12 (s, 1H),4.47 (d, J=8.5, 1H); ¹³C NMR (CD₃OD, 100 MHz): 16.1, 16.6, 17.9, 37.3,38.6, 57.3, 64.8, 67.4, 69.4, 71.7, 75.8, 83.9, 108.3, 177.4, 180.2; IR(NaCl, cm⁻¹): 1772 s (C═O), 3410 br (O—H); MS Found: 295.0 (M+1), Calc.294.11; Mp 249.5-250° C.

[0183] (±)-Merrilactone A (1). The procedure of Fukuyama et al.^(5b) wasessentially followed. The mixture of epoxides 2 and 2a (133 mg) wasstirred with TsOH.H₂O (80 mg, 0.42 mmol) in 25 mL of CH₂Cl₂ for 1 day atRT. The TsOH.H₂O was filtered off and washed 3 times with CH₂Cl₂. Thecrude product was adsorbed on silica gel (ca. 0.5 g) and chromatographed(CH₂Cl₂/AcOEt 4:1, then 2:1, then 1:1) to give 14 mg (11% from alcohol30) of somewhat impure minor epoxide 2a followed by (±)-merrilactone A(92 mg, 71% from alcohol 30). Minor epoxide 2a: ¹H NMR (CD₃OD, 300 MHz):δ 1.10 (s, 3H), 1.13 (d, J=0.7, 3H), 1.49 (s, 3H), 1.93 (dd, J=16.2,J=2.2, 1H), 2.39 (d, J=16.2, 1H), 2.82 (d, j=19.0, 1H), 3.28 (d, J=19.0,1H), 3.40 (d, J 2.2, 1H), 3.74 (d, J=9.0, 1H), 4.14 (s, 1H), 5.20 (d,J=9.0, 1H); ¹³C NMR (CD₃OD, 75 MHz): 16.0, 17.0, 17.8, 37.4, 41.7, 64.2,65.5, 68.0, 73.4, 88.0, 107.4, 176.6, 180.2; IR (NaCl, cm⁻¹): 1772 s(C═O), 3450 br (O—H); MS Found: 295.0 (M+1), Calc. 294.11; MerrilactoneA: ¹H NMR (CD₃OD, 400 MHz): δ 1.08 (s, 3H), 1.23 (s, 3H), 1.48 (s, 3H),2.28 (dd, J=15.4, J=1.5, 1H), 2.68 (d, J=19.4, 1H), 2.70 (d, J=5.2, 1H),2.73 (d, J=5.2, 1H), 2.90 (d, J=19.4, 1H), 3.94 (dd, J=5.2, J=1.5, 1H),4.01 (d, J=10.1, 1H), 4.59 (d, J=10.1, 1H), 4.73 (s, 1H); ¹³C NMR(CD₃OD, 75 MHz): 16.0, 17.4, 17.4, 32.2, 43.9, 58.5, 61.2, 66.0, 75.5,79.9, 90.3, 96.2, 107.3, 177.7, 179.3; IR (NaCl, cm⁻¹): 1761 s (C═O),3450 br (O—H); MS Found: 295.0 (M+1), Calc. 294.11; Mp 233.5-234.5° C.(from EtOAc/CHCl₃).

Example 2

[0184] The schemes above have been adapted to synthesizing nitrogencontaining Merrilactone analogues having the general structure:

[0185] wherein Z is >N—X, where X is straight or branched substituted orunsubstituted alkyl, alkenyl or alkynyl, or cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, amino, alkyl amino, or dialkylamino.

[0186] The basic modification which resulted in such analogues wassimply the replacing of the starting material

[0187] with a nitrogen containing starting material such as

[0188] and alkylating, e.g. methylating, the resulting Diels-Alderadduct.

REFERENCES

[0189] (1) Hefti, F. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 239.

[0190] (2) (a) Siegel, G. J.; Chauhan, N. B. Brain Res. Rev. 2000, 33,199; (b) Gash, D. M.; Zhang, Z.; Ovadia, A.; Cass, W. A.; Yi, A.;Simmerman, L.; Russel, D.; Martin, D.; Lapchak, P. A.; Collins, F.;Hoffer, B. J.; Gerhardt, G. A. Nature, 1996, 380, 252.

[0191] (3) Backman, C.; Rose, G. M.; Hoffer, B. J.; Henry, M. A.;Bartus, R. T.; Friden, P.; Granholm, A. C. J. Neurosci. 1996, 16, 5437.

[0192] (4) For a discussion of small molecule mimetics and forreferences to neurotrophic natural products, see: Ref.1, pp.255-257.

[0193] (5) (a) Huang, J. -m.; Yokoyama, R.; Yang, C. -s.; Fukuyama, Y.Tetrahedron Lett. 2000, 41, 6111 (b) Huang, J. -m.; Yang, C. -s.;Tanaka, M.; Fukuyama, Y. Tetrahedron 2001, 57, 4691.

[0194] (6) (a) Marinovic, N. N.; Ramanathan, H. Tetrahedron Lett. 1983,24, 1871; (b) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev.1991, 91, 1237.

[0195] (7) DMMA itself is capable of reacting only with the mostreactive dienes: (a) Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J.Am. Chem. Soc. 1980, 102, 6893 and references cited therein; (b) Rae, I.D.; Serelis, A. K.; Aust. J. Chem. 1990, 43, 1941; (c) von Ziegler, K.;Flaig, W.; and Velling, G. Liebigs Ann. 1950, 567, 204.

[0196] (8) Defoin, A.; Pires, J.; Streith, J. Helv. Chim. Acta 1991, 74,1665.

[0197] (9) (a) Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647;(b) Alexandre, F. -R.; Legoupy, S.; Huet, F. Tetrahedron 2000, 56, 3921.

[0198] (10) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R.K.; Timmers, F. J. Organometallics 1996, 15, 1518.

[0199] (11) Jaeschke, G.; Seebach, D. J. Org. Chem. 1998, 63, 1190.

[0200] (12) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret,P.; Keck, G. E.; Gras, J. L. J. Am. Chem. Soc. 1978, 100, 8031.

[0201] (13) Ward, D. E.; Rhee, C. K. Can. J. Chem. 1989, 67, 1210.

[0202] (14) (a) Johnson, W. S.; Wertheman, L.; Bartlett, W. R.; Lee, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741;(b) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227.

[0203] (15) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.

[0204] (16) (a) Rauscher, S. Tetrahedron Lett. 1977, 44, 3909.

[0205] (17) Henbest, H. B.; Wilson, R. A. L. Chem. Ind. (London) 1956,659.

What is claimed:
 1. A compound having the structure

wherein Z is O or >N—X, where X is H, straight or branched substitutedor unsubstituted alkyl, alkenyl or alkynyl, or acyl, carbamoyl,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, amino, alkylamino, or dialkyl amino; wherein each of R₁ and R₂ is H or R₁ and R₂together are ═O; wherein each of R₃ and R₄ is H or R₃ and R₄ togetherare ═O; wherein each of R₅ and R₆ is, independently, H, alkyl, aralkyl,or aryl; wherein each of R₇ and R₈ is, independently, H or OR₁₄, whereR₁₄ is alkyl or —C(O)—R₁₅, where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆,—CR₁₆R₁₇R₁₆, —OR₁₆, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, amino, alkyl amino, or dialkylamino, wherein each R₁₆ is straight or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, or amino; and wherein R₁₇ isstraight or branched, unsubstituted alkyl, alkenyl or alkynyl,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, or amino, orwherein R₇ and R₉ together are >O; wherein each of R₉ and R₁₀ is,independently, H, alkyl, OH, or OR₁₃, where R₁₃ is an alkyl, an acyl, oran amide, or R₉ and R₁₀ together are ═CH₂, or wherein R₈ and R₁₀together are >O; wherein if one of R₇ or R₈ and one of R₉ or R₁₀ isabsent, a double bond is formed as indicated by the broken line; andwherein each of R₁, and R₁₂ is, independently, H, OH, or OR₁₃, where R₁₃is an alkyl, an acyl, or an amide, or R₁, and R₁₂ together are ═O, orwherein R₁₂ and R₁₀ together are >O.
 2. The compound of claim 1, whereinZ is >N—X, where X is H, straight or branched substituted orunsubstituted alkyl, alkenyl or alkynyl, or acyl, carbamoyl, cycloalkyl,aryl, heterocycloalkyl, heteroaryl, aralkyl, amino, alkyl amino, ordialkyl amino.
 3. The compound of claim 1, wherein Z is O or >N—X, whereX is H, straight or branched alkyl, alkenyl or alkynyl, or acyl,carbamoyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl,amino, alkyl amino, or dialkyl amino; wherein each of R₁ and R₂ is H orR₁ and R₂ together are ═O; wherein each of R₃ and R₄ is H or R₃ and R₄together are ═O; wherein each of R₅ and R₆ is, independently, H, alkyl,or aralkyl; wherein each of R₇ and R₈ is, independently, H or OR₁₄,where R₁₄ is alkyl or —C(O)—R₁₅, where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆,—CR₁₆R₁₇R₁₆, —OR₁₆, cycloalkyl, aryl, or aralkyl, wherein each R₁₆ isalkyl, cycloalkyl, or aryl, aralkyl; and wherein R₁₇ is alkyl,cycloalkyl, aryl, or aralkyl, or wherein R₇ and R₉ together are >O;wherein each of, R₉ and R₁₀ is, independently, H, alkyl, OH, or OR₁₃,where R₁₃ is an alkyl, an acyl, or an amide, or R₉ and R₁₀ together are═CH₂, or wherein R₈ and R₁₀ together are >O; wherein if one of R₇ or R₈and one of R₉ or R₁₀ is absent, a double bond is formed as indicated bythe broken line; and wherein each of R₁₁ and R₁₂ is, independently, H,OH, or OR₁₃, where R₁₃ is an alkyl, an acyl, or an amide, or R₁₁ and R₁₂together are ═O, or wherein R₁₂ and R₁₀ together are >O.
 4. The compoundof claim 1 having the structure

wherein Z is >O; wherein each of R₁ and R₂ is H, or R₁ and R₂ togetherare ═O; wherein each of R₃ and R₄ is H, or R₃ and R₄ together are ═O;wherein each of R₅ and R₆ is, independently, H, alkyl, aralkyl, or aryl;wherein each of R₇ and R₈ is, independently, H or OR₁₄, where R₁₄ isalkyl or —C(O)—R₁₅, where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆, —CR₁₆R₁₇R₁₆,—OR₁₆, alkenyl or alkynyl, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, aralkyl, amino, alkyl amino, or dialkyl amino, wherein eachR₁₆ is straight or branched, substituted or unsubstituted alkyl, alkenylor alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, oramino; and wherein R₁₇ is straight or branched, unsubstituted alkyl,alkenyl or alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,aralkyl, or amino; and wherein R₉ is H, alkyl, OH, or OR₁₃, where R₁₃ isan alkyl, an acyl, or an amide.
 5. The compound of claim 4, wherein R₉is H, alkyl or OR₁₃, where R₁₃ is an alkyl, an acyl, or an amide.
 6. Thecompound of claim 4, wherein R₁ and R₂ together are ═O; wherein each ofR₃ and R₄ is H; wherein each of R₅ and R₆ is, independently, H, alkyl,or aralkyl; wherein each of R₇ and R₈ is, independently, H or OR₁₄,where R₁₄ is alkyl or —C(O)—R₁₅, where R₁₅ is H, —CH₂R₁₆, —CHR₁₆R₁₆,—CR₁₆R₁₇R₁₆, —OR₁₆, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, amino, alkyl amino, or dialkylamino, wherein each R₁₆ is straight or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, aralkyl, or amino; and wherein R₁₇ isstraight or branched, unsubstituted alkyl, alkenyl or alkynyl,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, or amino; andwherein R₉ is alkyl.
 7. A compound having the structure

wherein Z is O or >N—X, where X is H, straight or branched substitutedor unsubstituted alkyl, alkenyl or alkynyl, or acyl, carbamoyl,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl, amino, alkylamino, or dialkyl amino; wherein each of R₁ and R₂ is H or R₁ and R₂together are ═O; wherein each of R₃ and R₄ is H or R₃ and R₄ togetherare ═O; wherein each of R₅ and R₆ is, independently, alkyl, aralkyl, oraryl; and where Q is H or a silyl protecting group.
 8. The compound ofclaim 7 having the structure


9. The compound of claim 7 having the structure


10. The compound of claim 8 having the structure


11. The compound of claim 9 having the structure


12. A compound having the structure

wherein each of Ra, Ra′, Rb, and Rb′ is independently H, alkyl, alkenyl,alkynyl, acyl, or carbamoyl, or either Ra and Rb or Ra′ and Rb′ togetherwith the carbons to which they are attached form a substituted orunsubstituted five or six member ring; and wherein each of Rc and Rc′is, independently, H, OH or OR, wherein R is alkyl, acyl or Q, where Qis a silyl protecting group, or both Rc and Rc′ together are ═O.
 13. Aprocess for producing the compound of claim 12, comprising treating acompound having the structure

where M is Br or I, with Bu₃SnH or tris-(trimethyl silyl)-silane((TMS)₃SiH) and a free radical initiator so as to thereby produce thecompound.
 14. The process of claim 13, wherein the compound has thestructure

where Q is a silyl protecting group; and where each of R′ and R″ isindependently alkyl, alkenyl, alkynyl, acyl, or carbamoyl, or R′ and R″together form a substituted or unsubstituted five or six member ring,and the compound treated has the structure

where M is Br or I.
 15. The method claim 13, wherein the compound hasthe structure

and the compound treated has the structure

where Q is a silyl protecting group; and where M is Br or I.
 16. Themethod claim 13, wherein the compound has the structure

and the compound being treated has the structure

wherein the treatment is with Bu₃SnH and AlBN, so as to thereby producethe compound.
 17. A process for synthesizing a compound having thestructure

comprising a) reacting a compound having the structure

where Q is a silyl protecting group, with a compound having thestructure

at a temperature of from about 140° C. to 230° C. to produce a compoundhaving the structure

b) reacting the compound of step a) with MeONa to produce

c) treating both products of step b) with ClCO₂Me to produce

d) treating both products of step c) with NaBH₄ to produce

e) treating the products of step d) with LiOH to produce

f) treating the product of step e) with O₃ followed by Bn₂NH*TFA toproduce

g) treating the product of step f) with NaBH₄ to produce

h) treating the product of step g) with MeC(OEt)₃ to produce

i) treating the product of step h) LiOH and I₂ and to produce

j) treating the product of step i) with allylSnBu₃ to produce

k) treating the product of step j) with LHMDS, TMSC1 and PhSeCl, andthen with PhSeBr and MeCN to produce

l) treating the product of step k) with O₃, CH₂Cl₂ and 1-hexene toproduce

m) treating the product of step l) with Bu₃SnH and AlBN to produce

n) treating the product of step m) with TsOH to produce

o) treating the product of step n) with mCPBA or a dimethyldioxirane toproduce

p) treating the product of step o) with an acid to produce the compound.18. A process for synthesizing a compound having the structure

comprising a) reacting a compound having the structure

with a compound having the structure

at a temperature of from about 160° C. to 180° C. to produce a compoundhaving the structure

b) reacting the compound of step a) with MeONa and MeOH to produce

c) treating both products of step b) with ClCO₂Me in THF to produce

d) treating both products of step c) with NaBH₄ and MeOH to produce

e) treating the products of step d) with aqueous LiOH to produce

f) treating the product of step e) first with O₃ and PPh₃, and then withBn₂NH*TFA in benzene to produce

g) treating the product of step f) with NaBH₄ and CH₂Cl₂ in MeOH toproduce

h) treating the product of step g) with MeC(OEt)₃ and PivOH to produce

i) treating the product of step h) first with aqueous LiOH and MeOH, andthen with I₂ and NaHCO₃ in THF to produce

j) treating the product of step i) with allylSnBu₃, AlBN and PhH toproduce

k) treating the product of step j) first with LHMDS, TMSCI and PhSeCl,and then with PhSeBr and MeCN to produce

l) treating the product of step k) first with 03, CH₂Cl₂ and 1-hexene,and then with PhH, NEt₃ under reflux conditions to produce

m) treating the product of step l) with Bu₃SnH and AlBN, and PhH toproduce

n) treating the product of step m) with aqueous TsOH and PhH underreflux conditions to produce

o) treating the product of step n) with mCPBA and CH₂Cl₂ to produce

p) treating the product of step o) with aqueous TsOH and CH₂Cl₂ toproduce the compound.